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Beyond a Boutique Genome
Faster, cheaper genome sequencing

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Computational biologists can sequence an individual's genome so fast that comparison among individuals of a species is becoming a reality. When that happens, it's possible to understand what causes disease, or how proteins function, or even what genes are active at different stages of development.

It took an international consortium of scientists years and several hundred million dollars to unravel the complete genetic code of a human being for the first time. In 2008, nearly a decade later, U.S. scientists sequenced James Watson’s genome in mere months. These days, thanks to swift strides in technology that have slashed the cost and time required for gene sequencing, having a readout of your own DNA is no longer just the perquisite of Nobel Prize winning scientific superstars. Now sequencing a genome takes a month and can be had for the cost of a new car.

Gene sequencing has gotten so fast and affordable that it’s moved beyond the study of single reference individuals. By obtaining more sequences, researchers can investigate genetic differences across populations, correlate them with observable traits, and uncover the footprints of evolution.

Berkeley professor John Taylor and colleagues N. Louise Glass in the Department of Plant and Microbial Biology and Rachel Brem of Molecular and Cell Biology are putting the latest sequencing technology to work in their studies of the model organism Neurospora, a bread mold. They are about halfway to their goal of sequencing 100 Neurospora genomes, and plan to make their genomes available to other scientists working on the fungus.

“It seems sort of a crime to have all these enormous amounts of data and only be using it for simple things.”

Faster and cheaper technologies are making genomic sequencing a standard part of the laboratory repertoire, Taylor says. The first Neurospora genome sequence cost $5 million to complete in 2003; the next two cost $400,000 apiece to sequence five years ago; and the most recent each cost about $600.

With the genomes of many individuals, scientists can study variation within a species in more detail than ever before, and attempt to correlate those differences with observable characteristics. In the case of Neurospora, Taylor and his colleagues investigate the genetic underpinnings of traits such as the organism’s growth rate, colony form, or food preference.

New sequencing technologies are also allowing scientists to study how evolution progresses on a genomic level. They are looking for the genetic changes that allow some organisms to better adapt to their environment, giving them a competitive edge.

“A signature of natural selection remains in the genome,” Taylor says. Fungi, for example, seem to be continually adding or deleting genes, and those changes can stick when they change food preferences. Taylor and his colleagues carried out a genetic study of the fungus that causes valley fever, which commonly infects people in desert regions of the Americas. They found the genetic traces of the organism’s shift from plant-based to animal-based hosts. “That’s natural selection,” Taylor says. “That’s evolution we can see.” Finding the genes enabling valley fever fungus and other pathogens to cause disease may lead to new ways of controlling their mayhem.

Sequencing technology can also be used as a technique to spy on gene activity. To convert genetic information into proteins, cells make templates made of RNA molecules. That means RNA levels reflect how often genes are being transcribed. Scientists once had to settle for relative comparisons between gene expression in different organisms or under different conditions. Now, says plant and microbial biology professor N. Louise Glass, new sequencing technologies produce data on the actual number of RNA copies being made. “It’s much easier to compare one experiment to another,” Glass says. “That’s a big plus.” This same technology also offers a window into development. “We can look at organisms at various stages of development and see what genes are active at those different stages,” Taylor says.

Steven Brenner, an associate professor in the Department of Plant and Microbial Biology, is studying the genome of the fruit fly to understand how proteins are built. In particular, he is revealing how redundant sequences of RNA are removed before protein synthesis begins. In cells, this work is performed by proteins called splicing factors. Most of the splice factors found in fruit flies are shared by humans. Brenner says that studying how they work should help reveal how genetic mutations can lead to disease—and ultimately, how those diseases could be treated or even prevented. Without the latest advances in sequencing technology, Brenner says, this research would be “completely unthinkable.”

“It seems sort of a crime to have all these enormous amounts of data and only be using it for simple things.”

Biologists once struggled to obtain any scraps of genetic information. The new availability of gene sequences, Glass says, means “you’re not going to want for data.” These days, the challenge is in managing and interpreting this tidal wave of genetic information. Computational tools, she adds, are essential to make sense of it all. “It seems a crime to have these enormous amounts of data and use it only for simple things,” Glass remarks. Indeed, says Taylor, “The biologists who are most in demand are those who have computational skills.”

The need for computational biologists will only rise as sequencing data arrives at an even faster pace. “Within fi ve years,” Taylor says, “you’ll be able to get the complete sequence of any organism you want for an amount you can aff ord.…The promise is that within a few years, you’ll be able to sequence a human in 15 minutes, for $100.”

An affordable genome brings the possibility of health care tailored to each patient’s DNA. “Medicine will be genomic,” he adds. “You’ll have a copy of your personal genome, and every week computational biologists will find a new correlation between certain genetic differences and your condition. You’re going to keep going back to your physician to get updated.”

“We’ll be able to understand an individual’s biology, understand what their risks may be and what they might do to have the healthiest possible lives,” Brenner says. That would be a boon for everyone, not just James Watson.

-Anna Davison


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